Hemophilia A is a devastating X-linked recessive bleeding disorder occurring in the general population at frequency of 1-2 in 10,000 male births. The disease is caused by genetic changes encoding the blood clotting Factor VIII protein (FVIII). FVIII serves as necessary co-factor for the Factor IXa proteolytic activation of Factor X. Factor X activates thrombin which cleaves fibrinogen into fibrin in order to polymerize and form a blood clot. Genetic changes lead to a deficiency or complete absence of the FVIII activity in plasma. The disease is manifested by soft tissue hematomas and hemarthroses causing life-long permanent disability, shortened life-span, and in some instances, death. Severely affected patients may experience spontaneous internal hemorrhages even without cause of any trauma.
FVIII peptide is significant because of its biochemical properties and pathway. Nearly all plasma FVIII circulates as a complex with von Willebrand factor which is believed to stabilize, protect, and escort the protein to the blood vessel injury site. It has been shown that the delivery of FVIII to the site of injury increases the generation of thrombin and strengthens the plug formed by platelets. FVIII is also relatively large in size and the activation of its precursor involves a tantalizing sequence of post-translational modifications. The processing of FVIII involves proteolytic cleavages at numerous sites as well as other covalent modifications, such as N- and O-linked glycosylation, disulfide bridge formation, tyrosine sulfation, and metal cation insertion. These modifications eventuate in active, but labile protein possessing a plasma half-life of only 8 to 10 hours. An increase of FVIII serum level alleviates the symptoms of severe hemophilia A, leading to less frequent bleeding.
Gene therapy, using viral or plasmid vectors, is a possible avenue for treating hemophilia A. Studies toward this end in animal models are ongoing. Replacement therapy was introduced in the late 1970s and remains the only therapy currently available for Hemophilia A. It requires catheter or intravenous infusion of FVIII protein to compensate for its endogenous deficiency. Alternatively, mild cases of hemophilia A can sometimes be managed by taking desmopressin, which releases stored factor VIII from blood vessel walls. Thus, there remains need for an effective, safe treatment for hemophilia A.